Osteoblasts are cells responsible for bone formation. These cells produce a matrix of osteoid, which is composed mainly of type 1 collagen, chondroitin sulfate and osteocalcin. Osteoblasts also mineralize this matrix, e.g., making use of zinc, copper and sodium.
Osteoblasts arise from osteoprogenitor cells located in the periosteum of bone and the bone marrow. Osteoprogenitors are immature progenitor cells that express the master regulatory transcription factor Cbfa1/Runx2. Osteoprogenitors are induced to differentiate into osteoblasts by various growth factors, including the bone morphogenetic proteins (BMPs), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF) and transforming growth factor beta (TGF-β). Once osteoprogenitors start to differentiate into osteoblasts, they begin to express a range of genetic markers including Osterix, Coll, BSP, M-CSF, ALP, and osteocalcin, osteopontin, and osteonectin.
Osteocalcin (Bone Gla Protein: BGP) is a small vitamin K dependent calcium binding protein that was first discovered by Price et al. ((1976) Proc. Natl. Acad. Sci. 73:3373-5). This protein is synthesized primarily by osteoblasts and ondontoblasts and comprises 15 to 20% of the non-collagenous protein of bone. Posner et al. ((1980) J. Biol. Chem. 255:8685-91) have shown that mature osteocalcin contains three carboxyglutamic acid residues which are formed by post-translational vitamin K-dependent modification of glutamic acid residues. These residues have been further shown to be involved in the ability of osteocalcin to bind calcium ions (Brozovic et al. (1976) Brit. J Haematol. 32:9).
Osteocalcin is the principal extracellular matrix protein in bone required for normal bone mineralization. Normal bone mineral density is a result of hydroxyapatite crystals containing extracellular calcium and phosphate within a protein matrix. Calcium deposition within the protein matrix involves osteocalcin produced by osteoblasts. Phosphate deposition within the protein matrix involves Tissue Non-Specific Alkaline Phosphatase (TNAP) which regulates extracellular concentrations of inorganic pyrophosphate (ppi), a natural inhibitor of hyroxyapatite crystals. Mutations in the TNAP gene result in hypophosphatasia, characterized by elevated extracellular concentrations of inorganic pyrophosphate, poorly mineralized bones, spontaneous fractures.
It is now known that osteocalcin synergistically activates calcium sensing receptor 2 (CaR2) in the presence of calcium. Accordingly, alterations in osteocalcin expression or activity play a key role in disorders related to CaR2 function. For example, disorders in which the interaction of osteocalcin and CaR2 play a role include but are not limited to sperm motility and viability, and metabolic bone disorders such as osteoporosis.
Osteoporosis is a systemic skeletal disorder characterized by reduced bone mineral density and increased risk of fracture. The two major etiologies of osteoporosis are increased osteoclast activity which breaks down and reduced osteoblast activity. These features occur in the post-menopausal state and after chronic corticosteroid use, as well as in idiopathic instances. Most of the current treatment strategies for osteoporosis are focussed on anti-resorptive agents, such as bisphosphonates, which inhibit the bone resorption activity of osteoclasts. Certain strategies, such as use of parathyroid hormone (PTH), focus on increasing osteoblast activity, which is measured using biomarkers for enhanced osteoblast activity such as osteocalcin and bone specific-alkaline phosphatase.